Repurposing the anthelmintic drug mebendazole in combination with radiation therapy in an isocitrate dehydrogenase mutant glioma model.

Background: Heterozygous point somatic mutation in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most common genetic alterations in malignant glioma. This diffusely infiltrating glioma frequently progresses, despite maximal resection, radiation therapy (RT), and sometimes chemotherapy. We previously identified a brain-penetrant anthelminthic drug, Mebendazole, as a potential repurposed therapy for malignant glioma. Here, we tested the effect of mebendazole in combination with ionizing RT, part of the standard care for high-grade malignant glioma, in an IDH-mutant model. Methods: This study utilized glioma cells from a patient with mutant IDH1, to test the effect of mebendazole in combination with radiation in vitro on cell proliferation, cell cycle, and the apoptosis pathway. An orthotopic IDH-mutant grade III malignant glioma model was employed for in vivo experiments. Results: Mebendazole, in nanomolar concentrations, reduced cell proliferation, increased caspase-dependent apoptosis, and increased the DNA damage marker, ɣH2AX. The combination of mebendazole with RT, further reduced cell growth, arrested cells in G2/M, and disrupted the cell cycle and DNA damage pathways. An IDH-mutant xenograft model subjected to mebendazole plus RT showed improved survival compared to either therapy alone. Conclusions: Mebendazole plus RT increased apoptosis and provided a survival benefit in the IDH-mutant mouse model, supporting future clinical testing.